安普克
化学
蛋白激酶A
激活剂(遗传学)
内质网
高脂血症
腺苷
AMP活化蛋白激酶
脂质代谢
一磷酸腺苷
药理学
生物化学
激酶
内分泌学
基因
生物
糖尿病
作者
Mingchao Wang,Zunsheng Han,Baoyan Fan,Kai Qu,Wenxuan Zhang,Wei Li,Jingya Li,Li Li,Jin Li,Hui Li,Song Wu,Dongmei Wang,Haibo Zhu
标识
DOI:10.1021/acs.jmedchem.3c01267
摘要
Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.
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